Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pre-B cell lines proliferating for several months on stromal cells in the presence of interleukin 7 (IL-7) were established from fetal liver of (NZB x NZW)F1 mice. They express the B lineage-specific markers PB76, B220, and VpreB, but do not express surface immunoglobulin (sIg). Upon removal of IL-7 from the culture, they differentiate to sIg+ B cells that can then be stimulated by lipopolysaccharide to become IgM-secreting cells. Transfer of these pre-B cell lines into SCID mice leads to hypergammaglobulinemia of IgM (600-900 micrograms/ml), IgG2a (1-3 mg/ml), and IgG3 (300-500 micrograms/ml) for the next 3-5 mo. The spleen appears populated with (NZB x NZW)F1-derived pre-B cells, few B cells, and many IgM and/or IgG-producing plasma cells. In contrast, SCID mice populated with pre-B cell lines of normal (C57BL/6 x DBA/2)F1 mouse fetal liver develop normal levels of serum IgM (approximately 100-300 micrograms/ml), almost no detectable levels of IgG, and no plasma cell hyperplasia. The (NZB x NZW)F1 pre-B cell-populated SCID mice contain elevated serum titers of IgG antinuclear autoantibodies, but no retroviral gp70-specific nor erythrocyte-specific autoantibodies. Up to 20% of the SCID mice develop proteinuria as a consequence of IgG deposits in the kidney glomeruli during a 7-mo period of observation. All signs of autoimmune disease seen in these mice are independent of the sex of the SCID host. This experimental system provides a distinction between the disease-determining (NZB x NZW)F1 genes, which are expressed in the B lymphocyte lineage and cause the development of the disease, from those expressed in other cell lineages which only modulate its progression.
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PMID:Development of autoimmune disease in SCID mice populated with long-term "in vitro" proliferating (NZB x NZW)F1 pre-B cells. 140 80

We investigated the capacity of five human monoclonal IgG anti-DNA antibodies derived from lupus patients to produce glomerular immune deposits. The hybridomas secreting these antibodies were administered intraperitoneally to severe combined immunodeficiency (SCID) mice. Three of the five antibodies (B3, 35.21, 33.C9) were detected in the kidneys, but only one (33.C9) deposited exclusively in the glomeruli in the mesangium and capillary wall, whereas the other two antibodies bound to nuclei both in the kidney and in other organs. The antibodies were tested against a variety of autoantigens by ELISA, the only unique feature of 33.C9 was that it also bound strongly to histones. There were no particular amino acid motif that was related to immunoglobulin deposition in the kidney. All the mice that had immunoglobulin deposited in the kidney, either extracellularly or intranuclearly developed 2 to 3+ proteinuria, whereas the other mice had only trace amounts of proteinuria. This study demonstrates that some human monoclonal IgG anti-dsDNA antibodies are capable of binding to the glomerulus while others can penetrate cells and bind to nuclei in vivo. Although no abnormal pathology was observed, proteinuria was detected, perhaps representing an early phase of disease. These results indicate that the affinity for dsDNA is not the sole determining factor governing the biological properties of human anti-DNA antibodies in vivo.
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PMID:Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice. 747 55

It has recently been found that in systemic lupus erythematosus (SLE), a multisystem inflammatory disorder characterized by autoantibody production and decreased cellular immune response, increased spontaneous production of IL-10 occurs. The immunomodulator AS101 (ammonium trichloro(dioxoethylene-0,0')tellurate) was previously shown to significantly decrease IL-10 levels in cancer patients and in murine models. This study shows that AS101 inhibits the development of SLE-related autoimmune pathological manifestations. AS101 decreased the spontaneous IL-10 production by mononuclear cells from SLE patients in vitro. In vivo, systemic injection of AS101 to SCID mice transplanted with mononuclear cells from SLE patients significantly decreased serum human IL-10 levels. There was also a decrease in all serum human Ig isotypes, in anti-dsDNA, and in anti-Sm Igs. In the New Zealand Black/New Zealand White/F1 model, AS101 significantly increased serum TNF-alpha and IFN-gamma while decreasing IL-10 levels; these changes were accompanied by a rapid decrease in anti-dsDNA and anti-ssDNA Igs. More importantly, continuous treatment of New Zealand Black/New Zealand White/F1 mice with AS101 for 6 mo led to the development of proteinuria in 30% of the treated mice compared with 100% in PBS-treated mice (p < 0.001). AS101 treatment reduced the level of immmune complex deposition in the glomeruli, prevented glomerular hypercellularity and mesangial expansion and led to a much smaller mean glomerular volume in treated mice (185 +/- 6 vs 428 +/- 47.103 microm3; p < 0.01). We suggest that treatment with a nontoxic immunomodulator such as AS101, previously used in phase II trials on cancer patients, may be an effective therapeutic approach for controlling SLE.
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PMID:Delay in the onset of systemic lupus erythematosus following treatment with the immunomodulator AS101: association with IL-10 inhibition and increase in TNF-alpha levels. 930 Jun 85

Antibodies binding to double-stranded (ds) DNA are strongly associated with renal involvement in patients with systemic lupus erythematosus (SLE). We have generated two new IgG DNA-binding monoclonal antibodies (mAb), RH-14 and DIL-6, from the peripheral blood lymphocytes of two SLE patients with glomerulonephritis using the heteromyeloma cell line CB-F7. RH-14 is an IgG1 lambda antibody which also bound to single-stranded DNA, histones and nucleosomes. DIL-6 is an IgG3 lambda antibody with restricted antigen binding specificity. cDNA encoding the variable regions of the heavy (V(H)) and light (V(L)) chains of RH-14 was sequenced and the antigen binding site of this mAb was computer modelled. Sequence analysis of V(H) and V(L) regions of RH-14 showed that V(H) is derived from germ-line gene V3-7, a member of the V(H)3 family, and V(L) is derived from DPL 11, a member of the V(lambda)2 family. Somatic mutations and basic amino acid residues are identified in the complementarity-determining regions of both V(H) and V(L) regions. The nephritogenic properties of these mAb were analyzed by implanting and growing the hybridoma cells secreting the mAb in the peritoneum of SCID mice. The animals that received the RH-14 hybridoma produced higher levels of proteinuria (3 to > or = 4) (p < 0.001) compared to the groups that received DIL-6 (trace to > or = 1) or CB-F7 (trace). Electron microscopy of kidney sections from all the RH-14-implanted animals showed granular immunoglobulin deposition in the renal glomerular capillaries and mesangium. In this study we have shown for the first time using electron microscopy that a human IgG anti-dsDNA mAb, RH-14, is nephritogenic and that deposition of such an antibody alone is sufficient to induce renal damage.
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PMID:Genetic, structural and functional properties of an IgG DNA-binding monoclonal antibody from a lupus patient with nephritis. 948 13

The pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN), the most prevalent form of glomerulonephritis worldwide, involves circulating macromolecular IgA1 complexes. However, the molecular mechanism(s) of the disease remain poorly understood. We report here the presence of circulating soluble FcalphaR (CD89)-IgA complexes in patients with IgAN. Soluble CD89 was identified as a glycoprotein with a 24-kD backbone that corresponds to the expected size of CD89 extracellular domains. To demonstrate their pathogenic role, we generated transgenic (Tg) mice expressing human CD89 on macrophage/monocytes, as no CD89 homologue is found in mice. These mice spontaneously developed massive mesangial IgA deposition, glomerular and interstitial macrophage infiltration, mesangial matrix expansion, hematuria, and mild proteinuria. The molecular mechanism was shown to involve soluble CD89 released after interaction with IgA. This release was independent of CD89 association with the FcRgamma chain. The disease was induced in recombination activating gene (RAG)2(-/-) mice by injection of serum from Tg mice, and in severe combined immunodeficiency (SCID)-Tg mice by injection of patients' IgA. Depletion of soluble CD89 from serum abolished this effect. These results reveal the key role of soluble CD89 in the pathogenesis of IgAN and provide an in vivo model that will be useful for developing new treatments.
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PMID:Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger's disease). Evidence for pathogenic soluble receptor-Iga complexes in patients and CD89 transgenic mice. 1083 14

There are few studies assessing the pathogenicity of human monoclonal anti-DNA antibodies. The use of SCID mice avoids the problem of rejection of the human hybridoma cells thus allowing in vivo assessment of human immunoglobulins. Using electron microscopy we have shown that the human IgG anti-dsDNA monoclonal antibody, RH14, is nephritogenic in SCID mice, causing morphological changes in the kidney due to immunoglobulin deposition. The problem with using SCID mice is that they have an abnormal immune system; normally they are used at about 2 months of age, at which time they have virtually no functional T or B cells. It is known that older SCID mice become increasingly 'leaky', that is they develop some mature lymphocyte clones. Our aim was to assess if implanting anti-DNA antibodies into older 'leaky' SCID mice would result in pathology which was observable by light microscopy. Eight-month-old SCID mice were implanted with human hybridoma cells secreting either RH14 an anti-dsDNA IgG, CL24, an antiphospholipid antibody or an irrelevant human IgG control. As previously, RH14 deposited in the kidney and caused proteinuria but unexpectedly we also observed hyaline thrombi in the kidney glomeruli and peritubular capillaries. These thrombi occurred only in the case of RH14 implanted mice and were found to stain positively for human IgG and fibrin. However, apart from the interesting thrombi, we did not observe any greater pathological damage resulting from the anti-dsDNA antibody deposition than we had seen in the younger mice; indeed, the electron microscopic findings were more limited.
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PMID:A human anti-dsDNA monoclonal antibody caused hyaline thrombi formation in kidneys of 'leaky' SCID mice. 1167 10

To investigate, whether T lymphocytes alone are sufficient to induce glomerulonephritis, a model in SCID mice was developed. Conditions for the generation and exclusive glomerular targeting of crosslinked ovalbumin (OVA) polymers and a series of OVA-specific T-cell clones and lines were established. Only a well-defined subfraction of OVA polymers exclusively targeted to the glomerular mesangium without causing local alteration in the absence of IgG. From numerous T-cell preparations spanning different Th-1/-2 profiles one T-helper cell clone characterized by ELISPOT assay as pure Th-1 (IFN-gamma and IL-2) induced nephritislike pathology. Histological examination at days 1, 2, 5, and 21 showed major infiltrates in proximal tubular regions (PTR) at day 5 accompanied by significant proteinuria. No injury was observed after deposition of irrelevant antigen or injection of other T-cell preparations. Detailed histological analysis revealed that Th-1 cell numbers peaked early in glomeruli (2.1 +/- 0.6 vs 0/gcs). Macrophages, however, were hardly detectable in glomeruli (0.5 +/- 0.3/gcs) at this time, while they formed the major constituent of the PTR infiltrates at day 5 (83 +/- 1). These data in a new SCID nephritis model indicate that memory Th-1 cells together with localized antigen presenting cells trigger nephritis.
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PMID:CD4+ T cells recognizing specific antigen deposited in glomeruli cause glomerulonephritis-like kidney injury. 1216 77

In order to develop a model in mouse similar to anti- Thy-1 nephritis in the rat, we prepared sheep antiserum against SV40-transformed mouse mesangial (MES 13) cells. In vivo, the anti-mouse mesangial cell serum-treated mice showed severe azotemia that peaked at day 6 and proteinuria that peaked at day 8, in a dose-dependent fashion. Light microscopy and electron microscopy showed duplication of glomerular basement membranes, mesangiolysis, subendothelial and mesangial electron-dense deposits, and foot process effacement. Intraglomerular tuft cell number was significantly reduced at day 4 and there were increased numbers of apoptotic cells at days 2 and 4. SCID mice and mice lacking C3 manifested similar responses to anti-mouse mesangial cell serum, suggesting that T cells, B cells and complement are not required for glomerular injury in this model. In vitro, anti-mouse mesangial cell serum treated mesangial cells showed greater release of lactate dehydrogenase, decreased cell survival, and increased apoptotic cell death. Anti-mouse mesangial cell serum induces glomerulopathy characterized by mesangiolysis and mesangial cell apoptosis, and followed by cellular proliferation.
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PMID:Anti-mouse mesangial cell serum induces acute glomerulonephropathy in mice. 1266 Apr 12

Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells.
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PMID:Induction of B7-1 in podocytes is associated with nephrotic syndrome. 1514 36

The fine binding characteristics of three well-characterized human autoantibodies B3, RH14 (anti-DNA) and UK4 (anti-cardiolipin) in their IgG and cloned Fab formats, were investigated. Although in severe combined immunodeficiency (SCID) mice B3 and RH14 both induce proteinuria, only RH14 induces early features of lupus nephritis, whereas UK4 exhibits lupus anticoagulant activity. RH14 exhibited up to 10 fold higher binding to DNA compared to that shown by B3 or UK4 and involved significant electrostatic and phosphate group interactions. Only RH14 exhibited strong anti-Sm cross-reactivity residing on the C-terminus of the antigen as determined by the use of 76 overlapping 15mer peptides. Chain shuffling experiments indicate that anti-Sm/RNP and anti-Jo-1 activities of B3 and UK4 co-exist on one of the two chains (light, B3; heavy, UK4). The present study provides evidence that a human anti-DNA antibody can also be an anti-ENA antibody. Furthermore, the anti-DNA antibodies also exhibited cross-reactivity against glutathione-S-transferase and DNA polymerase PolIV of bacterial origin. This is the first demonstration of the presence of such cross-reactivities on lupus anti-DNA antibodies. We now demonstrate that subsets of sera from the patients with lupus, recognise these antigens. This observation may in some cases provide a mechanism for the common expression of a variety of autoantibodies observed in systemic lupus erythematosus (SLE).
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PMID:Fine binding characteristics of human autoantibodies-partial molecular characterization. 1518 28


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